DESCRIPTION: A variety of K channels regulate he action potential in cardiac cells. The HERG channel is unusual in that its primary structure resembles that of many depolarization-activated channels, such as Shaker, whereas functionally it displays properties of the inward rectifier. The inward rectification, however, seems to derive from intrinsic gating properties, rather than the more common blockade mechanism. The proposed research will analyze the gating of exogenously expressed human HERG channels, and the effects of channel blockers. The specific aims are to elucidate the biophysical and molecular mechanisms that account for the voltage-dependent behavior of HERG and to examine the mechanisms of interaction with various pharmacological inhibitors.